The overall goal of this research is to characterize neuroendocrine and cellular factors responsible for the enhanced efficiency of dietary energy retention in obesity-prone animals. The genetically obese (ob/ob) mouse will be used in most of the proposed studies. This animal has a mutation in the ob gene that leads to production of a truncated and presumably nonfunctional ob protein in adipose tissue. Wild-type ob protein is secreted from adipose tissue to regulate food intake and energy balance. One hypothesis to be tested is that mutation of the ob gene in ob/ob mice leads to altered regulation in the central nervous system of the neuropeptide Y and corticotropin releasing hormone systems, and that these alterations also depend on the presence of glucocorticoids or selected dietary factors including dietary glucose or fat. Studies are proposed to determine how intracerebroventricular injection of dexamethasone and/or wild-type ob protein into adrenalectomized ob/ob mice fed various diets affects neuropeptide V and corticotropin releasing hormone secretion in selected hypothalamic sites. In parallel studies hypothalamic blocks from adrenalectomized ob/ob mice will be treated in vitro with dexamethasone and/or ob protein. Neuropeptide Y and corticotropin releasing hormone secretion will be measured. Another hypothesis to be tested is that the ob gene mutation causes an early developmental imprint in pancreatic islets that leads to a persistent defect in regulation of insulin secretion distal to glucose-induced insulin secretion per se. Pancreatic islets from 2 wk old ob/ob and lean mice will be cultured to characterize the metabolic basis for this defect. Islets from neonatal ob/ob and +/+ mice will be examined to see if an imprint is expressed between birth and 2 wk of age in ob/ob mice. These data should increase our understanding of the diet and neurohormonal-dependent metabolic factors that interact with ob protein in regulation of body fatness, and should aid in defining improved nutritional approaches to the prevention and control of obesity.